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Randomized Trial of the Combination of Lomeguatrib and Temozolomide Compared With Temozolomide Alone in Chemotherapy Naive Patients With Metastatic Cutaneous Melanoma

Malcolm Ranson, Peter Hersey, Damien Thompson, Jane Beith, Grant A. McArthur, Andrew Haydon, Ian D. Davis, Richard F. Kefford, Peter Mortimer, Peter A. Harris, Sofia Baka, Augustus Seebaran, Ami Sabharwal, Amanda J. Watson, Geoffrey P. Margison, Mark R. Middleton

From the Department of Medical Oncology, University of Manchester; Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester; Kudos Pharmaceuticals, Cambridge; Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford, United Kingdom; Princess Alexandra Hospital, Brisbane; Newcastle Melanoma Unit, Newcastle; Royal Prince Alfred Hospital; Westmead Institute for Cancer Research, University of Sydney at Westmead, Millenium Institute, Sydney; Peter MacCallum Cancer Centre; The Alfred Hospital; and Austin Health, Melbourne, Australia

Address reprint requests to Mark R. Middleton, MD, PhD, Cancer Research UK Medical Oncology Unit, Churchill Hospital, Old Rd, Oxford, OX3 7LJ, United Kingdom; e-mail: mark.middleton{at}cancer.org.uk

Purpose To evaluate tumor response, pharmacodynamic effects, and safety of a combination of lomeguatrib (LM), an O⁶-methylguanine DNA-methyltransferase (MGMT) inactivator, and temozolomide (TMZ), TMZ alone, and LM/TMZ after disease progression on TMZ alone in patients with advanced melanoma.

Patients and Methods Patients with unresectable stage III or IV cutaneous melanoma who had no prior systemic chemotherapy were randomly assigned to receive either 40 to 80 mg LM and 125 mg/m² TMZ or 200 mg/m² TMZ on days 1 through 5 of each 28-day treatment cycle. Drugs were administered orally for up to six cycles of treatment. Patients on TMZ alone were offered LM/TMZ at progression, if fit enough to receive treatment.

Results One hundred four patients were enrolled, with 52 in each trial arm. Twenty-seven TMZ-treated patients received LM/TMZ after progression on TMZ. Unexpectedly, analysis of tumor biopsies showed rapid recovery of MGMT after LM/TMZ with 40 mg/d LM. Therefore, doses of LM were escalated to 60 then 80 mg/d. Tumor response rates were 13.5% with LM/TMZ and 17.3% with TMZ alone. No patient responded to LM/TMZ having progressed through TMZ. Median time to disease progression was 65.5 days for LM/TMZ and 68 days for TMZ. All treatments were well tolerated, although hematologic and gastrointestinal adverse events were common. A higher incidence of hematological adverse events was observed in the LM/TMZ combination arm.

Conclusion The efficacy of LM and TMZ in the current dosing schedule is similar to that of TMZ alone. To maintain MGMT depletion in tumor dosing of LM needs to be continued beyond that of TMZ.

Supported by Kudos Pharmaceuticals, owned by AstraZeneca.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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